Cancer stemness in hepatocellular carcinoma: mechanisms and translational potential

Abstract

Cancer stemness, referring to the stem-cell-like phenotype of cancer cells, has been recognised to play important roles in different aspects of hepatocarcinogenesis. A number of well-established cell-surface markers already exist for liver cancer stem cells, with potential new markers of liver cancer stem cells being identified. Both genetic and epigenetic factors that affect various signalling pathways are known to contribute to cancer stemness. In addition, the tumour microenvironment-both physical and cellular-is known to play an important role in regulating cancer stemness, and the potential interaction between cancer stem cells and their microenvironment has provided insight into the regulation of the tumour-initiating ability as well as the cellular plasticity of liver CSCs. Potential specific therapeutic targeting of liver cancer stemness is also discussed. With increased knowledge, effective druggable targets might be identified, with the aim of improving treatment outcome by reducing chemoresistance.

Fig. 1. Identification of functionally important lncRNAs responsible for supporting liver cancer stemness.

The use of microarray analyses for identifying lncRNAs downregulated in cisplatin-resistant hepatospheres or lncRNAs enriched in CD133⁺CD13⁺ hepatospheres. lncRNAs could support liver cancer stemness by modulating a range of signalling pathways critical in normal development and stem cells.

Fig. 2. Key signalling pathways that support liver cancer stem cell properties and their association with liver cancer stem cell marker expression.

Wnt/β-catenin and IL-6/STAT3 are the two main signalling pathways that support liver cancer stemness. Recent studies have provided additional evidence that MAPK signaling, NF-κB signaling, Hippo signaling, and Notch signaling are also playing critical roles in supporting liver cancer stemness and associated with the elevated expression of the indicated liver cancer stem cell markers.

Fig. 3. The plasticity of LCSCs refers to the acquisition of the necessary changes in cell states to facilitate the adaptation of LSCSs to the tumour microenvironment.

This includes plasticity in the form of EMT, metabolic reprogramming and differentiation plasticity. EMT refers to the change from epithelial to mesenchymal states of the cells. Metabolic reprogramming shifts the reliance on glucose and aerobic glycolysis to enhanced mitochondrial respiration and fatty acid oxidation. Differentiation plasticity allows the expansion of hepatic progenitor cells (HPCs) and promotes stemness gene expression. All of these support HCC formation.

Fig. 4. Key cellular components (upper part) and physical influences (lower part) in the liver tumour microenvironment that support stemness gene expression and tumour initiation.

Cellular components include CAFs, TAMs, T cells, B cells and the respective secreted cytokines and factors. The physical components consist of ECM and the hypoxic environment. All of these play roles in promoting stemness gene expression to drive the tumour-initiation activity of LCSCs.